Over the past few years a growing understanding of the specific mechanisms that HIV-1 uses to enter target cells has emerged. This facilitated efforts to develop drugs that attack discrete steps in this process. The first drug to target entry has recently been approved for clinical use (enfuvirtide, T20; A. Lazzarin et al., N. Engl J. Med. (2003) 348:2186-95). Enfuvirtide is a peptide drug that blocks fusion at a stage subsequent to chemokine receptor binding.
HIV-1 infection is initiated by interactions between the viral envelope glycoprotein (Env) and a cellular receptor complex comprised of CD4 plus a chemokine receptor (T. C. Pierson and R. W. Doms, Immuno. Lett. (2003) 85:113-18; and J. M. Kilby and J. J. Eron, N. Engl. J. Med. (2003) 348:2228-38). Env has two subunits: the surface glycoprotein gp120 which interacts with the cellular CD4-receptors and which is non-covalently associated with the virus transmembrane subunit gp41. Gp41 anchors gp120 to the viral membrane, and is also responsible for fusion. Binding of gp120 to CD4 on cells triggers a conformational change that exposes or creates a binding site that enables gp120 to interact with a cell surface chemokine receptor, the “co-receptor”. Chemokine receptors are seven transmembrane G-protein coupled receptors (7 TM GPCRs) that normally transmit signals in response to chemokines, small cytokines with chemotactic, inflammatory and other functions.
A large proportion of drugs in clinical use are directed at other 7TM GPCRs, and so targeting these molecules to block viral entry is an extension of the most successful type of drug development programs of the past. HIV-1 isolates require CD4 and a coreceptor to enter and infect cells. The CC chemokine receptor CCR5 is a co-receptor for macrophage-tropic (R5) strains and plays a crucial role in the sexual transmission of HIV-1 (E. A. Berger, AIDS(1997) 11(Suppl. A):S3-S16; P. D. Bieniasz and B. R. Cullen, Frontiers in Bioscience (1998) 3:44-58; D. R. Littman, Cell (1998) 93:677-680).
CCR5 is used by most HIV-1 primary isolates and is critical for the establishment and maintenance of infection. In addition CCR5 function is dispensable for human health. A mutant CCR5 allele, “CCR5Δ32”, encodes a truncated, non-functional protein (M. Samson et al., Nature (1996) 382:722-25; M. Dean et al., Science (1996) 273:1856-62). Individuals homozygous for the mutation lack CCR5 expression and are strongly protected from HIV-1 infection. They demonstrate no overt phenotype consequence and are highly resistant to M tropic HIV infection, whereas heterozygote individuals present delayed disease progression (M. K. Schwarz and T. N. Wells, Nat. Rev. Drug Discov. (2002) 1:347-58). The lack of CCR5 is without apparent adverse consequences, probably because CCR5 is part of a highly redundant chemokine network as receptor for the α chemokines MIP-1α, MIP-1β and RANTES, which share many overlapping functions, and most of which have alternative receptors (D. Rossi and A. Zlotnik, Annu. Rev. Immunol. (2000) 18:217-243). The identification of CCR5 as an HIV-1 co-receptor was based on the ability of its ligands, MIP-1α, MIP-1β and RANTES to block infection by R5 but not R5X4 or X4 isolates (F. Cocchi et al., Science (1995) 270:1811-15).
CCR5 is also a receptor of the “cluster” chemokines that are produced primarily during inflammatory responses and control the recruitment of neutrophils (CXC chemokines) and macrophages and subsets of T cells. (T helper Th1 and Th2 cells). Th1 responses are typically those involving cell-mediated immunity effective against viruses and tumors, for example, whereas Th2 responses are believed to be pivotal in allergies. Therefore, inhibitors of these chemokine receptors may be useful as immunomodulators. For Th1 responses, overactive responses are dampened, for example, in autoimmunity including rheumatoid arthritis or, for Th2 responses, to lessen asthma attacks or allergic responses including atopic dermatitis. (see e.g. D. Schols, Curr. Top. Med. Chem. (2004) 4:883-893; A. Mueller and P. G. Strange, Int. J. Biochem. Cell Biol. (2004) 36:35-38; W. M. Kazmierski et al., Curr. Drug Targets Infect. Disord. (2002) 2:265-278; T. Lehner, Trends Immunol. (2002) 23:347-51).
Antibodies against CCR5 are e.g. PRO 140 (W. C. Olson et al., J. Virol. (1999) 73:4145-55) and 2D7 (M. Samson et al., J. Biol. Chem (1997) 272:24934-41). Additonal antibodies are mentioned in US2004-0043033, U.S. Pat. No. 6,610,834, US2003-0228306, US2003-0195348, US2003-0166870, US2003-0166024, US2003-0165988, US2003-0152913, US2003-0100058, US2003-0099645, US2003-0049251, US2003-0044411, US2003-0003440, U.S. Pat. No. 6,528,625, US2002-0147147, US2002-0146415, US2002-0106374, US2002-0061834, US2002-0048786, US2001-0000241, EP1322332, EP1263791, EP1207202, EP1161456, EP1144006, WO2003/072766, WO2003/066830, WO2003/033666, WO02/083172, WO02/22077, WO01/58916, WO01/58915, WO01/43779, and WO01/42308.